scholarly journals Role of epithelial sodium channels in the regulation of lung fluid homeostasis

2015 ◽  
Vol 309 (11) ◽  
pp. L1229-L1238 ◽  
Author(s):  
Sadis Matalon ◽  
Rafal Bartoszewski ◽  
James F. Collawn
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Fetal Lung ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Airway Epithelial ◽  
Lung Fluid ◽  
Lung Epithelial ◽  
Distal Lung

In utero, fetal lung epithelial cells actively secrete Cl− ions into the lung air spaces while Na+ ions follow passively to maintain electroneutrality. This process, driven by an electrochemical gradient generated by the Na+-K+-ATPase, is responsible for the secretion of fetal fluid that is essential for normal lung development. Shortly before birth, a significant upregulation of amiloride-sensitive epithelial channels (ENaCs) on the apical side of the lung epithelial cells results in upregulation of active Na+ transport. This process is critical for the reabsorption of fetal lung fluid and the establishment of optimum gas exchange. In the adult lung, active Na+ reabsorption across distal lung epithelial cells limits the degree of alveolar edema in patients with acute lung injury and cardiogenic edema. Cl− ions are transported either paracellularly or transcellularly to preserve electroneutrality. An increase in Cl− secretion across the distal lung epithelium has been reported following an acute increase in left atrial pressure and may result in pulmonary edema. In contrast, airway epithelial cells secrete Cl− through apical cystic fibrosis transmembrane conductance regulator and Ca2+-activated Cl− channels and absorb Na+. Thus the coordinated action of Cl− secretion and Na+ absorption is essential for maintenance of the volume of epithelial lining fluid that, in turn, maximizes mucociliary clearance and facilitates clearance of bacteria and debris from the lungs. Any factor that interferes with Na+ or Cl− transport or dramatically upregulates ENaC activity in airway epithelial cells has been associated with lung diseases such as cystic fibrosis or chronic obstructive lung disease. In this review we focus on the role of the ENaC, the mechanisms involved in ENaC regulation, and how ENaC dysregulation can lead to lung pathology.

pH-regulated chloride secretion in fetal lung epithelia

2000 ◽  
Vol 278 (6) ◽  
pp. L1248-L1255 ◽  
Author(s):  
Carol J. Blaisdell ◽  
Rebecca D. Edmonds ◽  
Xi-Tao Wang ◽  
Sandra Guggino ◽  
Pamela L. Zeitlin
Keyword(s):  
Epithelial Cells ◽  
Short Circuit ◽  
Fetal Lung ◽  
Chloride Secretion ◽  
Lung Epithelial Cells ◽  
Apical Surface ◽  
Ussing Chambers ◽  
Lung Fluid ◽  
Lung Epithelial ◽  
Distal Lung

The fetal lung actively transports chloride across the airway epithelium. ClC-2, a pH-activated chloride channel, is highly expressed in the fetal lung and is located on the apical surface of the developing respiratory epithelium. Our goal was to determine whether acidic pH could stimulate chloride secretion in fetal rat distal lung epithelial cells mounted in Ussing chambers. A series of acidic solutions stimulated equivalent short-circuit current ( I eq) from a baseline of 28 ± 4.8 (pH 7.4) to 70 ± 5 (pH 6.2), 114 ± 12.8 (pH 5.0), and 164 ± 19.2 (pH 3.8) μA/cm2. These changes in I eq were inhibited by 1 mM cadmium chloride and did not result in large changes in [3H]mannitol paracellular flux. Immunofluorescent detection by confocal microscopy revealed that ClC-2 is expressed along the luminal surface of polarized fetal distal lung epithelial cells. These data suggest that the acidic environment of the fetal lung fluid could activate chloride channels contributing to fetal lung fluid production and that the changes in I eqseen in these Ussing studies may be due to stimulation of ClC-2.

Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells

2008 ◽  
Vol 294 (3) ◽  
pp. L478-L488 ◽  
Author(s):  
Aruna Kode ◽  
Saravanan Rajendrasozhan ◽  
Samuel Caito ◽  
Se-Ran Yang ◽  
Ian L. Megson ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Posttranslational Modifications ◽  
Nuclear Translocation ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Oxygen Species ◽  
Airway Epithelial ◽  
Alveolar Epithelial ◽  
Lung Epithelial

Nuclear erythroid-related factor 2 (Nrf2), a redox-sensitive transcription factor, is involved in transcriptional regulation of many antioxidant genes, including glutamate-cysteine ligase (GCL). Cigarette smoke (CS) is known to cause oxidative stress and deplete glutathione (GSH) levels in alveolar epithelial cells. We hypothesized that resveratrol, a polyphenolic phytoalexin, has antioxidant signaling properties by inducing GSH biosynthesis via the activation of Nrf2 and protects lung epithelial cells against CS-mediated oxidative stress. Treatment of human primary small airway epithelial and human alveolar epithelial (A549) cells with CS extract (CSE) dose dependently decreased GSH levels and GCL activity, effects that were associated with enhanced production of reactive oxygen species. Resveratrol restored CSE-depleted GSH levels by upregulation of GCL via activation of Nrf2 and also quenched CSE-induced release of reactive oxygen species. Interestingly, CSE failed to induce nuclear translocation of Nrf2 in A549 and small airway epithelial cells. On the contrary, Nrf2 was localized in the cytosol of alveolar and airway epithelial cells due to CSE-mediated posttranslational modifications such as aldehyde/carbonyl adduct formation and nitration. On the other hand, resveratrol attenuated CSE-mediated Nrf2 modifications, thereby inducing its nuclear translocation associated with GCL gene transcription, as demonstrated by GCL-promoter reporter and Nrf2 small interfering RNA approaches. Thus resveratrol attenuates CSE-mediated GSH depletion by inducing GSH synthesis and protects epithelial cells by reversing CSE-induced posttranslational modifications of Nrf2. These data may have implications in dietary modulation of antioxidants in treatment of chronic obstructive pulmonary disease.

PAR-2 activation and LPS synergistically enhance inflammatory signaling in airway epithelial cells by raising PAR expression level and interleukin-8 release

2007 ◽  
Vol 293 (5) ◽  
pp. L1208-L1218 ◽  
Author(s):  
Ewa Ostrowska ◽  
Elena Sokolova ◽  
Georg Reiser
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Expression Level ◽  
Epithelial Cell Line ◽  
Airway Epithelial ◽  
Protease Activated Receptors ◽  
Lung Epithelial ◽  
Epithelial Cell Lines

Protease-activated receptors (PARs) are involved in the contribution of airway epithelial cells to the development of inflammation by release of pro- and anti-inflammatory mediators. Here, we evaluated in epithelial cells the influence of LPS and continuous PAR activation on PAR expression level and the release of the proinflammatory chemokine IL-8. We studied primary human small airway epithelial cells and two airway epithelial cell lines, A549 and HBE cells. LPS specifically upregulated expression of PAR-2 but not of PAR-1. Exposure of epithelial cells to PAR-1 or PAR-2 agonists increased the PAR-1 expression level. The PAR-2 agonist exhibited higher potency than PAR-1 activators. However, the combined exposure of epithelial cells to LPS and PAR agonists abrogated the PAR-1 upregulation. The PAR-2 expression level was also upregulated after exposure to PAR-1 or PAR-2 agonists. This elevation was higher than the effect of PAR agonists on the PAR-1 level. In contrast to the PAR-1 level, the PAR-2 level remained elevated under concomitant stimulation with LPS and PAR-2 agonist. Furthermore, activation of PAR-2, but not of PAR-1, caused production of IL-8 from the epithelial cells. Interestingly, both in the epithelial cell line and in primary epithelial cells, there was a potentiation of the stimulation of the IL-8 synthesis and release by PAR-2 agonist together with LPS. In summary, these results underline the important role of PAR-2 in human lung epithelial cells. Moreover, our study shows an intricate interplay between LPS and PAR agonists in affecting PAR regulation and IL-8 production.

scholarly journals Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function

2015 ◽  
Vol 309 (1) ◽  
pp. L27-L36 ◽  
Author(s):  
Thomas E. Sussan ◽  
Sachin Gajghate ◽  
Samit Chatterjee ◽  
Pooja Mandke ◽  
Sarah McCormick ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cells ◽  
Allergic Asthma ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Related Factor ◽  
Airway Epithelial ◽  
Zonula Occludens ◽  
Lung Epithelial ◽  
Zonula Occludens 1

Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 ( Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47–59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2′-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.

scholarly journals Vitamin C Enhances Antiviral Functions of Lung Epithelial Cells

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1148
Author(s):  
Trevor Teafatiller ◽  
Sudhanshu Agrawal ◽  
Gabriela De Robles ◽  
Farah Rahmatpanah ◽  
Veedamali S. Subramanian ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Vitamin C ◽  
Bronchial Epithelium ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Airway Epithelial ◽  
Limited Information ◽  
Interferon Stimulated Genes ◽  
Lung Epithelial ◽  
Multiple Levels

Vitamin C is well documented to have antiviral functions; however, there is limited information about its effect on airway epithelial cells—the first cells to encounter infections. Here, we examined the effect of vitamin C on human bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) cells, and observed that sodium-dependent vitamin C transporter 2 (SVCT2) was the primary vitamin C transporter. Transcriptomic analysis revealed that treating BEAS-2B cells with vitamin C led to a significant upregulation of several metabolic pathways and interferon-stimulated genes (ISGs) along with a downregulation of pathways involved in lung injury and inflammation. Remarkably, vitamin C also enhanced the expression of the viral-sensing receptors retinoic acid-inducible gene 1 (RIG-1) and melanoma differentiation-associated protein 5 (MDA-5), which was confirmed at the protein and functional levels. In addition, the lungs of l-gulono-γ-lactone oxidase knockout (GULO-KO) mice also displayed a marked decrease in these genes compared to wild-type controls. Collectively, our findings indicate that vitamin C acts at multiple levels to exert its antiviral and protective functions in the lungs.

scholarly journals Intelectin is required for IL-13-induced monocyte chemotactic protein-1 and -3 expression in lung epithelial cells and promotes allergic airway inflammation

2010 ◽  
Vol 298 (3) ◽  
pp. L290-L296 ◽  
Author(s):  
Naibing Gu ◽  
Guannan Kang ◽  
Chang'E Jin ◽  
Yongjian Xu ◽  
Zhenxiang Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Inflammation ◽  
Airway Epithelium ◽  
Allergic Airway Inflammation ◽  
Airway Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Airway Epithelial ◽  
Chemotactic Protein ◽  
Lung Epithelial

Asthma is characterized by airway inflammation, mucus overproduction, airway hyperreactivity, and peribronchial fibrosis. Intelectin has been shown to be increased in airway epithelium of asthmatics. However, the role of intelectin in the pathogenesis of asthma is unknown. Airway epithelial cells can secrete chemokines such as monocyte chemotactic protein (MCP)-1 and -3 that play crucial roles in asthmatic airway inflammation. We hypothesized that intelectin plays a role in allergic airway inflammation by regulating chemokine expression. In a mouse allergic asthma model, we found that mRNA expression of intelectin-2 as well as MCP-1 and -3 in mouse lung was increased very early (within 2 h) after allergen challenge. Expression of intelectin protein was localized to mucous cells in airway epithelium. Treatment of MLE12 mouse lung epithelial cells with interleukin IL-13, a critical mediator of allergic airway disease, induced expression of intelectin-1 and -2 as well as MCP-1 and -3. When IL-13-induced intelectin-1 and -2 expression was inhibited by RNA interference, IL-13-induced extracellular signal-regulated kinase 1/2 phosphorylation and MCP-1 and -3 production by MLE12 cells was inhibited. Furthermore, inhibition of intelectin expression by airway transfection with shRNA targeting intelectin-1 and -2 attenuated allergen-induced airway inflammation. We conclude that intelectin, a molecule expressed by airway epithelial cells and upregulated in asthma, is required for IL-13-induced MCP-1 and -3 production in mouse lung epithelial cells and contributes to allergic airway inflammation.

Regulation of miR-155 biogenesis in cystic fibrosis lung epithelial cells: Antagonistic role of two mRNA-destabilizing proteins, KSRP and TTP

2013 ◽  
Vol 433 (4) ◽  
pp. 484-488 ◽  
Author(s):  
Sharmistha Bhattacharyya ◽  
Parameet Kumar ◽  
Motohiro Tsuchiya ◽  
Anirban Bhattacharyya ◽  
Roopa Biswas
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Cystic Fibrosis Lung ◽  
Lung Epithelial
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